Genetic Variant RNF126:p.Gly224Val (chr19-648487-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_194460.3(RNF126):c.671G>T(p.Gly224Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,764 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G224D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RNF126
NM_194460.3 missense, splice_region

Scores

Splicing: ADA: 0.9388

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.36

Publications

0 publications found

Variant links:

Genes affected

RNF126 (HGNC:21151): (ring finger protein 126) The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. [provided by RefSeq, Jul 2008]

RNF126 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF126	NM_194460.3 link	c.671G>T	p.Gly224Val	missense_variant, splice_region_variant	Exon 8 of 9	ENST00000292363.10	NP_919442.1	Q9BV68A0A024R206A8K0Q1
RNF126	NM_001366018.1 link	c.590G>T	p.Gly197Val	missense_variant, splice_region_variant	Exon 8 of 9		NP_001352947.1
RNF126	XM_047439069.1 link	c.*1G>T		splice_region_variant	Exon 8 of 8		XP_047295025.1
RNF126	XM_047439069.1 link	c.*1G>T		3_prime_UTR_variant	Exon 8 of 8		XP_047295025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF126	ENST00000292363.10 link	c.671G>T	p.Gly224Val	missense_variant, splice_region_variant	Exon 8 of 9	1	NM_194460.3	ENSP00000292363.3		Q9BV68

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414764

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700758

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32028

American (AMR)

AF:

0.00

AC:

AN:

39474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25502

East Asian (EAS)

AF:

0.00

AC:

AN:

36650

South Asian (SAS)

AF:

0.00

AC:

AN:

80604

European-Finnish (FIN)

AF:

0.0000221

AC:

AN:

45230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4154

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092470

Other (OTH)

AF:

0.00

AC:

AN:

58652

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000358

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.044

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.028

Eigen_PC

Benign

-0.042

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.39

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

2.4

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-4.3

D;.

REVEL

Benign

0.17

Sift

Uncertain

0.015

D;.

Sift4G

Uncertain

0.036

D;.

Vest4

0.40

MutPred

0.41

Loss of disorder (P = 0.0568);.;

MVP

0.40

MPC

0.31

ClinPred

0.93

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over